Primary mediastinal large B cell lymphoma

INTRODUCTION — Primary mediastinal large B cell lymphoma (PMBL) is an aggressive B cell lymphoma that is thought to arise from thymic (medullary) B cells. It has clinicopathologic features that are distinct from systemic diffuse large B cell lymphoma (DLBCL) and shares some clinical and biologic features with nodular sclerosing classic Hodgkin lymphoma (cHL).

This topic will discuss the clinical presentation, pathologic features, diagnosis, and treatment of PMBL. The diagnosis and treatment of systemic DLBCL and HL are presented separately. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma" and "Initial treatment of limited stage diffuse large B cell lymphoma".)

EPIDEMIOLOGY — PMBL comprises 7 percent of diffuse large B cell lymphomas (2.4 percent of all non-Hodgkin lymphomas) [1,2]. There is a female predominance and a median age at diagnosis in the third to fourth decade [3].

CLINICAL PRESENTATION

Oncologic emergencies — Patients present with a locally invasive anterior mediastinal mass originating in the thymus, with frequent airway compromise and superior vena cava (SVC) syndrome (image 1 and image 2) [4]. In one report of 30 patients, for example, SVC syndrome was present in 57 percent at presentation [5]. In addition, other patients without clinical SVC obstruction had evidence of compression of this vessel by computed tomography (CT) scan; in total, 80 percent had some evidence of SVC compromise. (See "Malignancy-related superior vena cava syndrome" and "Pathology of mediastinal tumors".)

Prompt recognition and management of SVC syndrome is critical. The clinical diagnosis of SVC syndrome is made on the basis of characteristic signs and symptoms of central venous obstruction. Dyspnea is the most common symptom. In addition, patients frequently complain of facial swelling or head fullness, which may be exacerbated by bending forward or lying down. Other symptoms include arm swelling, cough, chest pain, or dysphagia. Patients with cerebral edema may have headaches and confusion that may progress to coma. The diagnosis and management of malignancy-related SVC syndrome is presented separately. (See "Malignancy-related superior vena cava syndrome", section on 'Clinical features'.)

Management of patients with SVC syndrome can be challenging, as intubation is difficult given the high pressures needed to maintain the airway. Although commonplace in the past, emergency radiation is no longer considered necessary for most patients. Radiation prior to biopsy may obscure the histologic diagnosis and may compromise the safe delivery of necessary chemotherapy by injuring the bone marrow in the sternum, ribs, and spine. Current management guidelines stress the importance of accurate histologic diagnosis prior to starting therapy. (See "Malignancy-related superior vena cava syndrome", section on 'Treatment'.)

Other potential oncologic emergencies include:

●Acute airway obstruction

●Pericardial tamponade

●Hyperuricemia and tumor lysis syndrome

●Thrombosis of major neck or superior thoracic veins

Patients with large mediastinal masses are at increased risk of respiratory or cardiac arrest during general anesthesia or heavy sedation. Patients who present with cardiorespiratory symptoms or radiographic evidence of tracheal obstruction are at greatest risk of perioperative respiratory morbidity.

Although it is uncommon in PMBL, tumor lysis syndrome (TLS) is an oncologic emergency caused by massive tumor cell lysis and the release of large amounts of potassium, phosphate, and uric acid into the systemic circulation. Deposition of uric acid and/or calcium phosphate crystals in the renal tubules can result in acute renal failure, which is usually anuric. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors" and "Tumor lysis syndrome: Prevention and treatment".)

Other signs and symptoms — As described above, patients present with a locally invasive anterior mediastinal mass originating in the thymus, with frequent airway compromise and SVC syndrome (image 1 and image 2) [4]. Other structures that are sometimes involved by direct extension include the lungs, pleura, and pericardium. Up to half of patients may have a pleural or pericardial effusion [6]. Symptoms related to the compression or invasion of local structures (ie, cough, dyspnea, dysphagia, hoarseness) are common.

A retrospective analysis of 153 patients found the following signs and symptoms at the time of diagnosis [6]:

●Elevated lactate dehydrogenase (LDH, 77 percent)

●Systemic B symptoms (ie, fever, night sweats, weight loss, 47 percent)

●Pleural or pericardial effusion (50 percent)

Approximately three-quarters of patients have stage I or II disease at the time of diagnosis. In approximately half of patients, the primary tumor measures >10 cm in greatest dimension, and therefore constitutes bulky disease [6]. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Systemic "B" symptoms'.)

While PMBL may spread to supraclavicular and cervical lymph nodes, it is quite unusual for PMBL to involve the bone marrow or distant lymph nodes at the time of initial presentation [7]. Another characteristic feature is that relapses tend to be extranodal; relatively common sites of relapse include the liver, gastrointestinal tract, kidneys, ovaries, and central nervous system.

Radiographic features — As described above, patients with PMBL usually present with a locally invasive anterior mediastinal mass originating in the thymus. There is a paucity of published data describing the findings on imaging studies.

A single institution retrospective study described findings on CT in 66 patients with mediastinal lymphoma, including 21 patients with PMBL [8]. Among patients with PMBL, the median size of the main mass was 9.7 cm and the following were the most common features:

●Enlarged mediastinal lymph nodes (67 percent)

●Vascular encasement (62 percent)

●Pleural effusion (57 percent)

●Ill-defined margins (52 percent)

●Pericardial effusion (48 percent)

●Surface lobulation (33 percent)

●Chest wall invasion (19 percent)

●Local extension into overlying skin (10 percent)

●Lung invasion (10 percent)

Of these features, vascular involvement by the tumor was the only finding on CT that was independently associated with a higher likelihood of PMBL rather than Hodgkin lymphoma or T cell lymphoblastic lymphoma, which also frequently present as mediastinal masses.

PATHOLOGIC FEATURES

Morphology — PMBL usually involves the thymus at presentation [9,10]. The tumor is comprised of large cells with variable nuclear features, resembling centroblasts, large centrocytes, or multilobated cells, often with pale or "clear" cytoplasm [7]. Less frequently, the tumor cells resemble immunoblasts. Reed-Sternberg (RS)-like cells may be seen, but if present comprise a minor fraction of the tumor cells. Many cases have fine, compartmentalizing sclerosis (picture 1). Further details on the morphology of centrocytes, centroblasts, and immunoblasts are presented separately. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Morphology'.)

Immunophenotype — The immunophenotype of PMBL can be confirmed by histochemistry or flow cytometry. The tumor cells typically express B cell-associated antigens (CD19, CD20, CD22, CD79a) and CD45, and are negative for CD5 and CD10 [10]. Weak expression of CD30 is often present. The tumor cells also stain for TRAF-1 and nuclear c-REL; these markers are often positive in only a subset of cells and are particularly likely to be positive in RS-like cells [11]. These two markers are rarely present in other forms of diffuse large B cell lymphoma, but are commonly expressed by the RS cells of classic Hodgkin lymphoma (cHL). Other markers that are relatively specific for PMBL are CD200, CD23, and MAL [12,13]. Of these markers, MAL appears to be particularly sensitive and specific for PMBL [14]. Unlike most B cell tumors (but like cHL RS cells), the tumors typically do not express immunoglobulins.

Genetic features — There is no single cytogenetic change that is typical or diagnostic of PMBL, although translocations involving the CIITA gene have been found in up to approximately 40 percent of cases [15,16]. Immunoglobulin heavy and light chain genes are rearranged. BCL2 is usually in the germline configuration and BCL6 rearrangements are uncommon [10,17-19]. Amplification of REL has been described in a minority of cases [20]. Hyperdiploid karyotypes, often with gains in the region on chromosome 9p containing the JAK2 gene and the genes encoding PD-L1 and PD-L2, which are ligands for the receptor PD-1 [21], which has a role in suppressing T cell function, have been noted. Gene expression profiling has shown a similarity between the cell lines of primary mediastinal large B cell lymphoma and cHL, a disorder with which it shares a number of clinical and laboratory features [22-24].

DNA sequencing has identified several recurrent mutations in PMBL that provide further evidence of the importance of JAK-STAT and NF-kB activation PMBL. These events include loss of function mutations in negative regulators of NF-kB (eg, TNFAIP3 and NFKBIE) and mutations in multiple components and regulators of JAK-STAT signaling [25].

DIAGNOSIS — The diagnosis of PMBL is made based upon pathologic evaluation of tumor tissue in the context of the characteristic clinical findings.

Obtaining tissue — One of the most difficult problems in the diagnosis of PMBL can be obtaining an adequate biopsy specimen. Due to the location of the tumor, an excisional tissue biopsy is usually not possible. Small biopsies may be non-diagnostic because the lesion is not sampled adequately or because crush artifact or extensive necrosis, fibrosis, or cystic change obscures the diagnostic lesion. Due to fibrosis (which is often extensive), needle aspirates are often paucicellular and do not provide sufficient numbers of well-preserved tumor cells to establish the diagnosis. Similarly, core biopsies often contain only fibrotic tissue or tumor cells that are disrupted and not diagnostically useful. Because of these potential confounding factors, a surgical biopsy is preferred. As a rule, the diagnostic biopsy should consist of the largest tissue sample that can be easily and safely acquired. (See "Approach to the adult patient with a mediastinal mass".)

Urgent surgery may be required to obtain adequate tissue in patients with oncologic emergencies. The most common methods used for surgical biopsy of the mediastinum include cervical mediastinoscopy, anterior mediastinotomy, or thoracoscopy, depending upon the location of the lesion. Intraoperative frozen sections are often used to determine if diagnostic tissue has been obtained. However, frozen section processing introduces artifacts, and additional tissue should also be obtained that is not subjected to frozen sectioning. A sample of tumor also may be set aside to be snap frozen for molecular analyses.

Further evaluation — Further evaluation of the patient with suspected PMBL includes imaging with a positron emission tomography/computed tomography (PET/CT) and a bone marrow biopsy. Patients with involvement of the bone marrow or distant lymph nodes likely have systemic lymphoma with secondary mediastinal involvement, rather than PMBL. (See 'Systemic lymphoma with secondary mediastinal involvement' below.)

Making the diagnosis — The diagnosis of PMBL is based on an evaluation of the tumor morphology and immunophenotyping interpreted in the context of the clinical presentation. As mentioned above, patients with PMBL may have locally extensive disease in the mediastinum, but usually do not have evidence of distant spread at initial presentation. Staining for pan-B cell markers, such as CD20 and CD79a, is sufficient to establish the diagnosis in many cases; additional stains for CD30, nuclear c-Rel, TRAF-1, MAL, CD200, and PD-L1 can be helpful in cases with atypical features.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of PMBL includes benign and malignant mediastinal tumors and, less commonly, infectious and inflammatory entities that may present with mediastinal involvement (eg, histoplasmosis and Castleman disease).

Systemic lymphoma with secondary mediastinal involvement — Systemic diffuse large B cell lymphoma (DLBCL) may secondarily involve the mediastinum and may be confused with PMBL. Systemic disease is usually confirmed on imaging studies and/or bone marrow biopsy. At diagnosis, PMBL may have spread to supraclavicular and cervical lymph nodes, and late in its course it has a curious propensity to involve viscera (eg, the kidney) and the central nervous system. However, if there is evidence of tumor in the bone marrow or involvement of more distant lymph nodes, the more likely diagnosis is systemic DLBCL with secondary mediastinal involvement [7]. Immunohistochemistry can also help distinguish between systemic DLBCL and PMBL. Unlike systemic DLBCL, PMBLs typically express CD30 (weak), TRAF-1, nuclear c-Rel, CD200, and MAL. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma".)

Nodular sclerosing classic Hodgkin lymphoma — Nodular sclerosing classic Hodgkin lymphoma (cHL) and PMBL share many clinical and pathologic features. They are both more common in young women and present with a large mediastinal mass. On biopsy, PMBL may have cells that resemble the neoplastic Reed-Sternberg (RS) cells of cHL. In addition, gene expression profiling has shown a similarity between the two entities, and genetic studies have shown overlapping driver mutations, including frequent amplifications of the PD-L1 and PD-L2 genes in both entities.

Immunophenotype can help to distinguish PMBL from cHL in most cases. In cHL, the neoplastic RS cells typically express CD15 (85 percent of cases) and high levels of CD30 (>99 percent of cases), and lack pan-B and pan-T cell antigens. In contrast, PMBL cells typically express pan-B cell antigens, have weak expression of CD30, frequently express MAL-1 and CD200, and only rarely express CD15. (See "Hodgkin lymphoma: Epidemiology and risk factors".)

There are occasional cases with combined features of PMBL and cHL, which likely reflect the pathogenic commonalities between these two entities. Such cases are often referred to as "gray-zone" lymphomas and are labeled "B cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma" in the World Health Organization classification system [26].

TREATMENT

Pretreatment evaluation — Prior to initiating therapy, a pretreatment evaluation must establish the extent and sites of disease, and the performance status of the patient. The pretreatment evaluation for patients with PMBL is the same as that of patients with diffuse large B cell lymphoma (DLBCL). This is discussed in more detail separately. (See "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Pretreatment evaluation'.)

Initial therapy

Choice of therapy — The optimal treatment of PMBL is unknown and there is variation in clinical practice. Whenever possible, young, otherwise healthy patients should be encouraged to enroll onto a clinical trial. Outside of a clinical trial, choice of treatment options largely depends on patient and tumor characteristics and clinician comfort. (See 'Clinical trials' below.)

Frequent involvement of the chest wall and the presence of pleural and pericardial effusions make staging challenging (table 1). Patients with PMBL can be generally classified for management purposes as having either limited stage or advanced stage disease. Limited stage disease can be contained within one irradiation field. In contrast, advanced stage disease refers to disease that cannot be contained within one irradiation field, such as bulky disease (>10 cm) or tumors associated with pericardial or pleural effusion. All patients are treated with induction chemoimmunotherapy. The use of radiation therapy (RT) as part of primary therapy is more controversial and depends largely upon the choice of induction chemoimmunotherapy and on whether disease is present outside of the chest.

●For most patients with limited stage PMBL, we suggest induction chemoimmunotherapy with one of the following:

•R-CHOP – Six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) (table 2) followed by involved-field RT.

•da-EPOCH – Six cycles of dose-adjusted (da)-EPOCH-R (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab) (table 3) without RT; there is limited or no role for RT after (da)-EPOCH-R [27] .

Our choice between these two regimens is usually based on whether we want to avoid RT in a specific patient. Treatment using da-EPOCH-R would be preferred for patients who wish to avoid RT, such as young (age <30 years) women with disease requiring irradiation of the breast tissue. Due to concerns regarding efficacy, we do not advocate the use of chemotherapy-only regimens in patients with the uncommon subtype, mediastinal gray zone lymphoma. We do not support the use of R-CHOP alone; fewer cycles of R-CHOP plus RT; or the use of other chemoimmunotherapy regimens.

●For most patients with advanced stage PMBL, we suggest induction chemoimmunotherapy with one of the following:

•Six cycles of R-CHOP (table 2); some experts treat with eight cycles. R-CHOP is followed by involved-field RT for those patients whose disease is confined to the chest. Experts disagree with regards to the use of RT in patients with disease that extends beyond the chest. While involved-field RT is thought to improve local control of bulky disease within the chest, it is not clear whether this translates into a survival benefit in patients with disease outside of the chest.

•Six cycles of da-EPOCH-R (table 3) without RT.

As with limited stage disease, a choice between these regimens for an individual patient is largely based on the potential risks of RT.

Chemoimmunotherapy — There have been no randomized trials investigating the choice of chemotherapy or the use of RT in patients with PMBL. Support for the use of various management strategies comes largely from retrospective analyses and uncontrolled prospective studies.

Treatment with either six cycles of R-CHOP plus involved-field RT or six to eight cycles of da-EPOCH-R (without RT) are acceptable treatment options for patients with PMBL. A choice between these two options must take into consideration the toxicity of the regimens and risk of RT. A preference for R-CHOP plus involved-field RT places a high value on the ease of administration and less short-term toxicity following R-CHOP. Patients who place a high value on the avoidance of RT and its potential long-term toxicities may prefer da-EPOCH-R.

Importantly, many of the retrospective studies of PMBL did not include rituximab in the treatment regimen. When compared with other forms of DLBCL, PMBL appears to have a higher rate of primary refractoriness and early relapse following CHOP-based therapy without rituximab and poor response rates with second line therapies [28-31]. However, addition of rituximab to the initial therapy of PMBL may overcome at least some of poor prognostic features of PMBL [32].

The following prospective trials have evaluated chemoimmunotherapy in PMBL:

●Patients with PMBL were included in the randomized MabThera International (MInT) Trial of CHOP-like chemotherapy with or without rituximab in patients younger than 60 years [33,34]. A subset analysis of the 87 patients with PMBL reported that rituximab treatment resulted in a significant increase in the rate of complete remission (CR; 90 versus 54 percent), decrease in the rate of primary progressive disease (3 versus 24 percent), and increase in three-year event-free survival (78 versus 52 percent) [35]. There was a trend towards increased overall survival (OS) at three years (89 versus 78 percent) that did not reach statistical significance but was similar in magnitude to the statistically significant survival benefit for patients with DLBCL overall. (See "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Treatment'.)

●The MInT protocol included involved field RT for patients with bulky or extranodal disease. Among the 87 patients with PMBL, 76 were eligible for RT and 61 received RT [35]. While the addition of RT deepened responses in 30 percent, it is unknown whether this improvement in response can be attributed to the RT or whether these residual masses would have resolved without further therapy. (See "Initial treatment of limited stage diffuse large B cell lymphoma", section on 'Combined modality therapy (CMT)'.)

●In a single center phase II prospective study, 51 patients with newly diagnosed PMBL were treated with six to eight cycles of da-EPOCH-R [36]. All patients received prophylaxis with filgrastim and trimethoprim-sulfamethoxazole. Severe neutropenia and thrombocytopenia occurred in 50 and 6 percent of cycles, respectively, and patients were hospitalized for neutropenic fever during 13 percent of cycles. Three patients had residual disease; two proceeded with mediastinal radiation and one was observed after excisional biopsy. After a median follow-up of 63 months, the estimated rates of event-free and OS at five years were 93 percent (95% CI 81-98 percent) and 97 percent (95% CI 81-99 percent), respectively.

●In a single-arm prospective study, all 24 patients with previously untreated mediastinal gray-zone lymphoma (cases that combine features of PMBL and classic Hodgkin lymphoma) treated with da-EPOCH-R achieved complete (19 cases) or partial (five cases) remission [37]. At a median follow-up of 59 months, event-free and OS rates were 62 and 74 percent, respectively.

Is radiation necessary? — As the prognosis of patients with PMBL has improved, research has focused on finding the right balance of treatment in order to minimize long-term complications while maintaining high cure rates. Potential long-term toxicities from radiation therapy (RT) to the mediastinum include hypothyroidism, accelerated atherosclerotic heart disease, and lung and breast cancer. As such, clinicians are interested in minimizing the dose and field of radiation (eg, involved site radiation) and in identifying populations that can be successfully treated without RT. Outside of clinical trials, the use of RT in the initial treatment of PMBL is controversial and depends largely upon the choice of induction chemoimmunotherapy and on whether disease is present outside of the chest. (See 'Choice of therapy' above.)

RT is commonly employed for patients with limited stage disease after treatment with R-CHOP. In contrast, RT may be omitted following initial treatment with da-EPOCH-R. The use of positron emission tomography (PET) imaging to determine the need for RT is experimental.

Residual metabolic activity following initial therapy is associated with worse outcomes. In an international prospective study (IELSG-26), central evaluation of post-induction PET scans of 115 patients with limited stage PMBL treated with an anthracycline-based chemoimmunotherapy regimen identified 54 PET-negative scans (Deauville 1) and 27 scans with residual uptake higher than the mediastinal blood pool but lower than the liver (Deauville 2) [38]. Most patients proceeded with RT regardless of PET results. When compared with patients with higher residual uptake, patients with Deauville 1 or 2 PET scans had improved progression-free survival (98 versus 82 percent) and OS (100 versus 91 percent) at five years.  

A randomized trial (NCT01599559) is evaluating whether patients with a complete metabolic response after R-CHOP omit RT.

EVALUATION OF RESPONSE — One month following the completion of planned therapy (or sooner if the outcome is unfavorable), the response to treatment should be documented by history, physical examination, and laboratory studies (complete blood count, lactate dehydrogenase, and biochemical profile). Positron emission tomography/computed tomography (PET/CT) should be obtained six to eight weeks after completion of chemotherapy and 12 weeks after the completion of radiation therapy [39]. PET/CT imaging obtained earlier than this is likely to demonstrate increased uptake due to an inflammatory reaction to treatment. In one study, PET/CT imaging had a positive predictive value of 17 percent and a negative predictive value of 100 percent for the detection of residual tumor [36].

Given its unusual initial presentation and location of disease, the response criteria used for other types of non-Hodgkin lymphoma may not apply. Instead, prospective studies have used the following criteria for response:

●Complete response – Disappearance of all clinical symptoms and radiographic or laboratory abnormalities, including bone marrow involvement, observed at diagnosis and the absence of any new abnormalities.

●Progressive disease – Appearance of new abnormalities associated with the disease or evident deterioration of the initial abnormalities associated with the disease.

●Stable disease – Failure to achieve a complete response and lack of progressive disease.

Patients with a complete response are seen at periodic intervals to monitor for treatment complications and to assess for possible relapse. The frequency and extent of these visits depend upon the comfort of both the patient and clinician. Our approach is similar to that which we use for other patients with diffuse large B cell lymphoma.

Any residual abnormality on PET/CT must be evaluated to distinguish between residual fibrosis and necrosis and active disease. This distinction can often be made by serial imaging studies over time since benign disease will remain stable or decrease in size, while persistent PMBL will at some time begin to increase in size. Biopsy is required to document residual or relapsed disease prior to proceeding with subsequent therapy.

RELAPSED OR REFRACTORY DISEASE — Relapsed disease refers to recurrence of PMBL after an initial complete response (CR). Relapses tend to be extranodal, including the liver, gastrointestinal tract, kidneys, ovaries, and central nervous system, and almost all occur within two years [40,41]. Primary refractory disease occurs when initial therapy fails to achieve a CR.

Relapsed or refractory (r/r) disease can be suggested by clinical findings, laboratory abnormalities, or imaging studies, but it must be confirmed by biopsy.

There is no consensus treatment for patients with r/r PMBL. Patients should be encouraged to participate in a clinical trial, when available.

Treatment choices are informed by prior therapy, medical fitness, institutional experience/resources, and patient preference. Our approach is similar to that for patients with r/r diffuse large B cell lymphoma (DLBCL). Options for treatment of r/r PMBL include:

●First relapse – For medically-fit patients with first relapse of PMBL ≥12 months after initial treatment, we generally treat with salvage chemoimmunotherapy. For patients who achieve CR or a very good partial response to salvage chemotherapy, we proceed to autologous hematopoietic cell transplantation (HCT) [28,42-45]; we do not offer autologous HCT for lesser responses. Some institutions reserve transplantation for patients ≤75 years.

For patients whose earlier treatment did not include radiation therapy (RT), we generally treat suitable disease with RT.

Immune checkpoint inhibitors can be effective.

●Primary refractory PMBL or early (<12 months) relapse – For patients with primary refractory disease, early relapse (eg, <12 months), or second or later relapse of PMBL, we favor treatment with chimeric antigen receptor (CAR)-T cell therapy, where available.

Treatment is generally palliative for patients with tumors that fail to respond to second-line chemotherapy and are not candidates for HCT, immunotherapy, or clinical trials. Lower-intensity chemoimmunotherapy and/or RT may be more suitable for palliation of symptoms in patients who are medically-unfit or who decline more aggressive approaches.

Details of treatment for r/r DLBCL are presented separately. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit" and "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit".)  

●Outcomes – There are limited reports of outcomes with relapsed PMBL in the rituximab era; patients with primary refractory disease generally fare worse [25].

•Autologous HCT – A single-institution retrospective study reported that among 43 patients with r/r PMBL who underwent autologous HCT, three-year overall survival (OS) was 65 percent and progression-free survival (PFS) was 60 percent; most patients received mediastinal RT prior to HCT [46]. Other reports have described 57 to 70 percent five-year OS with autologous HCT for PMBL [40,41,47].

•Immune checkpoint inhibitors – PD-L1 is often expressed by the tumor cells in PMBL and immune checkpoint inhibitors have demonstrated benefit for r/r PMBL.

-Pembrolizumab – Treatment with pembrolizumab was associated with 45 percent overall response rate (ORR; 13 percent CR) among 53 patients with r/r PMBL in the phase 2 KEYNOTE-170 study and 41 percent ORR (33 percent CR) among 21 patients in an earlier phase 1 study (KEYNOTE-013); median PFS was 6 months and 10 months, respectively [48,49]. Pembrolizumab was used as a bridge to transplantation in nine patients in KEYNOTE-170. Approximately one-quarter of patients treated with pembrolizumab had grade ≥3 adverse events (AEs; eg, neutropenia).

-Nivolumab with brentuximab vedotin (BV) – The combination of the checkpoint inhibitor nivolumab with brentuximab vedotin (anti-CD30-drug immunoconjugate) was highly active in this setting (Check-Mate 436 study) [50]. ORR was 70 percent (43 percent CR) and with follow-up of 11 months, median OS was not reached. Half of the patients proceeded to HCT. Grade ≥3 AEs occurred in half, with the most common being neutropenia (30 percent) and peripheral neuropathy (10 percent).

The US Food and Drug Administration (FDA) approved pembrolizumab in r/r PMBL for treatment of adult and pediatric patients who have relapsed after ≥2 lines of therapy.

In other diseases in which patients treated with pembrolizumab later proceeded to allogeneic HCT, there were high rates of transplant-related complications, such as hyperacute graft-versus-host disease (GVHD), severe acute GVHD, steroid-requiring febrile syndrome, hepatic sinusoidal obstruction syndrome (veno-occlusive disease), and other immune-related adverse reactions. The risk of these complications in patients with PMBL is unknown. (See "Toxicities associated with immune checkpoint inhibitors".)

•CAR-T cell therapy – CD19-directed CAR-T cell therapy has substantial activity against r/r PMBL.

-Axicabtagene ciloleucel (axi-cel) – Treatment of eight patients with axi-cel for r/r PMBL was associated with 71 percent ORR (12 percent CR); for all 119 patients in the study (including those with transformed follicular lymphoma), median PFS was six months [51]. In a follow-up report with 27 month median follow-up, ongoing responses were maintained in five of eight cases of PMBL [52].

-Lisocabtagene maraleucel (liso-cel) – Treatment of 14 patients with r/r PMBL with lisocabtagene was associated with 79 percent ORR [53].

Axi-cel and liso-cel have been approved by the US FDA for treatment of r/r PMBL after two lines of therapy, including autologous HCT, and for primary refractory PMBL.

CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

PROGNOSIS — Cure rates for PMBL with aggressive therapy, usually combining chemotherapy with mediastinal irradiation are similar to those for diffuse large B cell lymphoma [3,5,54]. However, if relapse or progression occurs, salvage therapy is rarely curative.

There is a paucity of biomarkers to predict which cases will have a more favorable or aggressive course. The international prognostic index (IPI) used for other non-Hodgkin lymphoma subtypes is not predictive in PMBL. Initial studies suggest that a more favorable course may be predicted by low tumor metabolic activity, as measured by decreased total lesion glycolysis (a measure of fluorodeoxyglucose [FDG] uptake) on FDG positron emission tomography (PET) imaging at baseline or after initial therapy [38,55]. Further study is needed to confirm the prognostic value of PET before it can be used to modify initial treatment plans.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lymphoma diagnosis and staging" and "Society guideline links: Management of diffuse large B cell lymphoma".)

SUMMARY AND RECOMMENDATIONS

●Primary large B cell lymphoma of the mediastinum (PMBL) is an aggressive tumor arising in the mediastinum from the thymic (medullary) B cell. It is a distinct clinicopathologic entity that differs from systemic diffuse large B cell lymphoma (DLBCL).

●PMBL typically affects persons in their third to fourth decade of life and has a female predominance. (See 'Epidemiology' above.)

●Patients present with a locally invasive anterior mediastinal mass that frequently extends into local structures, resulting in superior vena cava syndrome, effusions, and symptoms of cough, dyspnea, dysphagia, and/or hoarseness. Systemic B symptoms and elevated lactate dehydrogenase levels are not uncommon. (See 'Clinical presentation' above.)

●The tumor is composed of large cells with variable nuclear features, resembling centroblasts, large centrocytes, or multilobated cells, often with pale or "clear" cytoplasm. The tumor cells typically express B cell-associated antigens (CD19, CD20, CD22, CD79a), CD45, CD30 (weak), TRAF-1, nuclear c-REL, MAL, CD200, and PD-L1 and typically fail to express immunoglobulin, CD5, and CD10. (See 'Pathologic features' above.)

●An adequate biopsy specimen is key to the diagnosis. A surgical biopsy is preferred to needle aspirates and core biopsies, since the latter often do not provide sufficient numbers of well-preserved cells. Further evaluation involves imaging studies and a bone marrow biopsy. The diagnosis is ultimately made based on an evaluation of the tumor morphology and immunophenotyping interpreted in the context of the clinical presentation. (See 'Diagnosis' above.)

●The differential diagnosis of PMBL includes benign and malignant tumors that present in the anterior mediastinum. The most difficult pathologic distinctions involve systemic lymphoma with secondary mediastinal involvement and classic Hodgkin lymphoma. (See 'Differential diagnosis' above.)

●We encourage participation in a clinical trial, when available. Outside of a clinical trial, a choice among treatment options largely depends upon patient and tumor characteristics. (See 'Initial therapy' above and 'Clinical trials' above.)

●For most patients with PMBL that can be contained within one irradiation field, we suggest treatment with either six cycles of R-CHOP (table 2) followed by involved-field radiotherapy (IFRT) or six to eight cycles of dose-adjusted (da)-EPOCH-R (table 3) without IFRT rather than R-CHOP alone; fewer cycles of R-CHOP plus RT; or the use of other chemoimmunotherapy regimens (Grade 2C).

Our choice between these two regimens is usually based on whether we want to avoid RT in a specific patient. da-EPOCH-R would be preferred for patients who wish to avoid RT, such as young (age <30 years) females with disease requiring irradiation of the breast tissue. In contrast, a preference for R-CHOP places a high value on the ease of administration and acceptable short-term toxicity. (See 'Initial therapy' above.)  

●For most patients with PMBL that cannot be contained within one irradiation field, we suggest induction chemoimmunotherapy with six cycles of R-CHOP or six to eight cycles of da-EPOCH-R (Grade 2C). R-CHOP is followed by IFRT for those patients whose disease is confined to the chest. IFRT is not used after da-EPOCH-R. (See 'Initial therapy' above.)

●Optimal therapy for patients with relapsed or refractory PMBL is not well defined. The general approach is to administer systemic chemotherapy with or without rituximab with plans to proceed to autologous hematopoietic cell transplantation (HCT) in patients with chemotherapy-sensitive disease; we generally do not offer autologous HCT to patients with PMBL that is refractory to chemotherapy. Treatment with an immune checkpoint inhibitor or chimeric antigen receptor (CAR)-T autologous cell immunotherapy are acceptable options. (See 'Relapsed or refractory disease' above.)